Hyperfibrinolysis is Associated with Complement Activation Following Trauma

Abstract

Background

Complement is activated after trauma, but the activation mechanism is unknown. Plasmin can directly activate C3 and C5, and four distinct fibrinolytic phenotypes have now been recognized after injury—hyperfibrinolysis, fibrinolysis shutdown, hypofibrinolysis, and nonpathologic/physiologic.

Objectives

We set out to investigate whether a relationship between complement activation and fibrinolysis was present in adult trauma patients (n = 56).

Methods

Rapid and tPA-challenged thromboelastography (TEG) was performed in the emergency department with IRB approval, and plasma obtained for C3a, C4a, C5a, Ba, sC5b-9, Factor I, Factor H, active PAI-1, α-2 antiplasmin (A2AP), plasmin-antiplasmin complex (PAP), and tPA activity measurement via multiplex, ELISA and activity assays. Data were analyzed using ANOVA and Spearman's correlations. Significance was set at p < 0.05.

Results

C3a and sC5b-9 were significantly higher in patients with hyperfibrinolysis than with physiologic or hypofibrinolysis (p < 0.05). Elevations in C3a, C4a, and SC5b9, along with depletion of Factors H and I, were significantly associated with massive transfusion within 6 hours and postinjury death. There were significant positive correlations between multiple markers of fibrinolysis and complement activation markers and significant negative correlations with Factors H and I. Significant negative correlations between fibrinolytic inhibitors and complement activation were also observed.

Conclusion

Our findings suggest that fibrinolysis may play a direct role in complement activation in trauma through plasmin-mediated cleavage of C3 and C5.

Keywords

complement - fibrinolysis - trauma - inflammation - tranexamic acid (TXA)

Authors' Contribution

C.D.B. and E.R.M. prepared the manuscript with critical input, data interpretation, and revisions from all other listed authors.

^* These authors are co-first author.

Publication History

Received: 15 November 2024

Accepted: 24 March 2025

Accepted Manuscript online:
25 March 2025

Article published online:
30 April 2025

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